Genetic Phenomena Commons^™

Structural-Functional Analyses Of The Huntingtin/Hap40 Complex In Drosophila And Humans, Stephen M Farmer, Amanda Solbach, Shiyu Xu, Beatriz Rios, Xin Ye, Amy Gao, Daniela Covarrubias, Yue Yu, Lili Ye, Vicky Chuong, Erin Furr Stimming, Haiqing Zhao, Sheng Zhang

Faculty, Staff and Student Publications

Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormal CAG expansion in the Huntingtin (HTT) gene. Given its simple genetic cause but complex pathogenic mechanisms, interest in targeting HTT for HD treatment is growing, necessitating a clear understanding of HTT regulation. HTT protein primarily exists in a core complex with HAP40, forming a highly ordered structure with two large globular domains connected by a bridge. We previously demonstrated that HAP40 is conserved in

Unraveling The Nexus: Tumor Mutational Burden, Pd-L1 Expression, And Oncogenic Alterations In Non-Small Cell Lung Cancer Cytology Specimens, Min Dai, Francis Anthony San Lucas, Hector Alvarez, Leomar Ballester, Hui Chen, Keyur P Patel, Asif Rashid, Shun Rao, Mark J Routbort, Gloria Sura, Keith Sweeney, Gokce Toruner, Peng Wei, Richard Yang, Hyvan Dang, Rajyalakshmi Luthra, Sinchita Roy-Chowdhuri

Faculty, Staff and Student Publications

Background: PD-L1 expression and tumor mutational burden (TMB) are biomarkers for immune checkpoint inhibitor (ICI) therapy in non-small cell lung cancer (NSCLC); however, patients harboring oncogenic alterations have limited benefit from ICIs. The impact of oncogenic alterations on TMB and PD-L1 tumor proportion score in lung cytology specimens is poorly understood. Herein, the association between oncogenic alterations, TMB, and PD-L1 in NSCLC cytology specimens is explored.

Methods: Next-generation sequencing results from 312 NSCLC cytology specimens were retrospectively reviewed that interrogate 610 genes and select immuno-oncology signatures. TMB and PD-L1 immunohistochemical expression across oncogenic alterations were analyzed to explore associations.

Results: …

Baseline Parp-1 Pet Imaging In Patients With Advanced Solid Tumors With Dna Damage Response Mutations, Tarek Daoud, Jiansong Chen, Peng Wei, Franklin Wong, Timothy A Yap, Lilie L Lin

Faculty, Staff and Student Publications

Purpose: Inhibitors of poly(ADP-ribose) polymerase (PARP), an enzyme with numerous roles in DNA damage response signaling, represent a class of anti-cancer drugs approved for treating solid tumors with defects in the DNA damage response. However, additional methods for identifying patients who would benefit from the use of PARP inhibitors are urgently needed. We evaluated a novel radiotracer, 18F-FluorThanatrace ([18F]-FTT), to noninvasively assess PARP activity with PET/CT before treatment and determine associations between uptake, tumor mutation status, and prior receipt of therapy including PARP inhibitors.

Methods: Fifty-two patients with solid tumors underwent whole-body (skull base to thigh) [18F]-FTT PET/CT scans before …

Tumor Flare Reaction With Brentuximab-Vedotin In Mycosis Fungoides, Rishabh Lohray, Seda Purnak, Samruddhi Arkatkar, Madeleine Duvic, Victor Prieto, Carlos Torres-Cabala, Auris Huen

Faculty, Staff and Student Publications

No abstract provided.

Identifying Sorafenib Benefit Among Patients With Hepatocellular Carcinoma: A Transcriptomic And Genomic Approach, Sun Young Yim, Hayeon Kim, Tae Hyung Kim, Sang-Hee Kang, Youngwoo Lee, Eunho Choi, Yang Jae Yoo, Seong Hee Kang, Young-Sun Lee, Young Kul Jung, Yeon Seok Seo, Hyung Joon Yim, Jong Eun Yeon, Kyung Suk Yang, Yitao Tang, Bowha Sohn, Yun Seong Jeong, Hyewon Park, Han Liang, Ju-Seog Lee, Ji Hoon Kim

Faculty, Staff and Student Publications

Background & aims: Sorafenib has been a cornerstone of hepatocellular carcinoma (HCC) therapy; however, its efficacy is limited, and identifying patients who will benefit from sorafenib is challenging. We aimed to identify predictive biomarkers of sorafenib benefit in patients with HCC.

Methods: Gene expression data from 33 HCC tumors treated with sorafenib were analyzed to construct a prediction model aimed at identifying patients with greater benefit from sorafenib treatment. The robustness of the predictor was validated using gene expression data from two phase III clinical trials, IMbrave150 and STORM.

Results: The analysis of transcriptome data revealed a 50-gene signature, the …

Axillary Management After Neoadjuvant Endocrine Therapy (Net), Laura Leonard, Min Yi, Emma Wingate, Puneet Singh, Abigail Caudle, Rosa F Hwang, Isabelle Bedrosian, Vicente Valero, Jennifer Litton, Nuhad Ibrahim, Kelly K Hunt

Faculty, Staff and Student Publications

BACKGROUND: In patients with hormone receptor-positive (HR

PATIENTS AND METHODS: We performed a retrospective review of patients with clinical stage I-III, HR

RESULTS: A total of 230 patients were included; 120 (52.2%) were clinically node-negative (cN0), while 110 (47.8%) were clinically node-positive (cN+). In the cN+ group, 7.3% (8/110) had a nodal pathologic complete response (pCR). In total, 76.4% (84/110) in the cN+ group underwent axillary lymph node dissection (ALND) as the initial axillary procedure, and 90.9% (100/110) underwent ALND overall. In total, 98.3% (118/120) with cN0 disease underwent sentinel lymph node dissection (SLND), and 28 (23.7%) had positive nodes. …

(Giga)Time For The Era Of Ai: Virtual Multiplex Immunofluorescence From Routine H&E For Large Populations, Shao-Ping Yang, Dihua Yu

Faculty, Staff and Student Publications

No abstract provided.

An Atlas Of Genetic Effects On The Monocyte Methylome Across European And African Populations, Wanheng Zhang, Chuan Qiu, Xiao Zhang, Zichen Zhang, Kuan-Jui Su, Zhe Luo, Minghui Liu, Bingxin Zhao, Lang Wu, Qing Tian, Hui Shen, Chong Wu, Hong-Wen Deng

Faculty, Staff and Student Publications

No abstract provided.

Monitoring Relapse In Post-Transplant Acute Myeloid Leukemia Requires Integrated Assessment, With Flow Cytometry Showing The Highest Efficacy, Wei J Wang, Sa A Wang, Hong Fang, Qing Wei, Shimin Hu, Sanam Loghavi, Gheath Al-Atrash, Chenxuan Zang, Peng Wei, Jeffrey L Medeiros, Wei Wang

Faculty, Staff and Student Publications

No abstract provided.

Fecal Carbohydrate-Degrading Bacteria Are Associated With Reduced Incidence Of Lower Gastrointestinal Gvhd, Christopher Fan, Tomo Hayase, Chia-Chi Chang, Israel K Glover, Ivonne I Flores, Lauren K Mcdaniel, Miriam R Ortega, Christopher A Sanchez, Rawan K El-Himri, Alexandria N Brown, Jennifer L Karmouch, Mohamed A Jamal, Saira S Ahmed, Taylor M Halsey, Yimei Jin, Wen-Bin Tsai, Rishika Prasad, Altai Enkhbayar, Aqsa Mohammed, Maren Schmiester, Ashish Damania, Nadim J Ajami, Jennifer A Wargo, Christine B Peterson, Gabriela Rondon, Taha Al-Juhaishi, Amin M Alousi, Jeffrey J Molldrem, Richard E Champlin, Elizabeth J Shpall, Eric Martens, Cesar A Arias, Robert R Jenq, Eiko Hayase

Faculty, Staff and Student Publications

Lower gastrointestinal graft-versus-host disease (LGI-GVHD) carries morbidity and mortality for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), with critical contributions from the intestinal microbiome. In a retrospective cohort of metagenomic sequencing of stool from patients with allo-HSCT (N = 90), we found that a reduction in specific Parabacteroides and Bacteroides species around the time of engraftment contributes to LGI-GVHD risk. Given the known diverse carbohydrate-degrading functionality of these bacteria, we investigated gene abundances for carbohydrate-active enzymes (CAZymes) and found that Parabacteroides merdae, P distasonis, and Bacteroides ovatus abundances were significantly correlated with CAZymes in patients who did not develop …

Genome-Wide Crispr Screen Identifies A Cytokine-Enhancer Circuit Driving Hif-2Α Activation In Renal Cancer, Jun Fang, Jeremy M Simon, Tao Wang, Yunpeng Gao, Xianju Bi, Lianxin Hu, Chengheng Liao, Cheng Zhang, Yayoi Adachi, Jin Zhou, Hongyi Liu, Qian Liang, James A Nathan, Ram Mani, James Brugarolas, Qing Zhang

Faculty, Staff and Student Publications

Resistance to HIF-2α inhibitors such as Belzutifan underscores the need to better understand how HIF-2α is transcriptionally regulated in clear cell renal cell carcinoma (ccRCC). Here, we uncover a cytokine-driven enhancer mechanism that sustains HIF-2α expression through the JAK1-STAT3 signaling pathway. Using a genome-wide CRISPR screen in VHL-deficient ccRCC cells, we identified SOCS3 as a key negative regulator of HIF-2α. Mechanistically, loss of SOCS3 activates JAK1-STAT3 signaling, leading to the recruitment of STAT3 to distal enhancers upstream of EPAS1 that physically loop to its promoter to drive HIF-2α transcription. This cytokine-enhancer circuit was recapitulated in ccRCC patient samples and functionally …

A Retrospective Analysis Of Taxane-Based Chemotherapy In Small Bowel Adenocarcinoma, Mir Lim, Nikhil Grandhi, Preksha Shah, Kanwal Raghav, Victoria Serpas, Maria Pia Morelli, Katrina Pedersen, Aparna Kalyan, Mohamed Salem, Ryan Huey, John Paul Shen, Huamin Wang, Hua Wang, Anjali Vinocha, Jane Thomas, Robert Wolff, Michael J Overman

Faculty, Staff and Student Publications

Background: Small bowel adenocarcinoma (SBA) is molecularly distinct from colorectal and gastric cancers, yet treatment typically parallels colorectal cancer. We evaluated the activity of taxane-based therapy in the largest SBA cohort to date.

Methods: We retrospectively reviewed SBA patients treated with taxane-based chemotherapy at MD Anderson Cancer Center from 1994-2024. Eligible patients had pathologic confirmation, received >1 treatment cycle, and had tumor response evaluation. Survival analyses were analyzed using Kaplan-Meier and Cox proportional hazard models.

Results: Seventy patients were identified. Median age was 57, and 59% were male. Primary sites were duodenum (44%), jejunum (34%), and Ileum (16%). Metastatic sites …

Integration Of Cross-Species Multi-Omics With In Vivo Experimental Validation Identifies Parkinson’S Disease Therapeutic Targets And Novel Risk Factors Within Endolysosomal Pathway Subnetworks, Justin Moore, Leo Rao, Sara Garcia-Bellido, Fangfei Guo, Jorge Botas, Juan Botas

Duncan NRI Faculty and Staff Publications

Parkinson's disease (PD), the most common neurodegenerative movement disorder, imposes a growing healthcare and socioeconomic burden worldwide. A defining hallmark of PD is the accumulation of α-synuclein (αSyn) within intracellular inclusions such as Lewy bodies and Lewy neurites. Genomic studies have identified numerous PD risk factors within the endolysosomal pathway (ELP), an essential cellular system for protein and membrane recycling. Concordantly, recurrent transcriptomic and proteomic alterations in ELP components implicate broad ELP dysfunction as a causal contributor to PD and suggest that additional, uncharacterized ELP genes may cooperate in polygenic disease mechanisms. A promising but underexplored therapeutic concept is that …

Evaluating Eight Smoking Metrics For Modelling Survival In Non-Small Cell Lung Cancer, Andrew Cl Lam, Yao Li, M Catherine Brown, Yangqing Deng, Katrina Hueniken, Natasha B Leighl, Frances A Shepherd, Kiera Murison, Zhichao Wang, Jui Kothari, Angela S Wenzlaff, Haoran Liu, Takashi Kohno, Angela Cecilia Pesatori, Curtis Harris, Hongxia Ma, Juncheng Dai, Matthew J Barnett, Ryan Diver, Leticia Ferro Leal, Guillermo Fernandez-Tardon, Mónica Pérez-Ríos, Michael Pa Davies, Bernd Holleczek, Paul Brennan, David Zaridze, Ivana Holcatova, Jolanta Lissowska, Beata Świątkowska, Dana Mates, Milan Savic, Hermann Brenner, Angeline S Andrew, Fiona Taylor, John K Field, Alberto Ruano-Ravina, Sanjay S Shete, Adonina Tardon, Ying Wang, Loic Le Marchand, Rui Manuel Reis, Matthew B Schabath, Marian L Neuhouser, Hongbing Shen, Maria Teresa Landi, Kouya Shiraishi, Jie Zhang, Ann G Schwartz, Ming S Tsao, David C Christiani, Ping Yang, Rayjean J Hung, Wei Xu, Geoffrey Liu

Faculty, Staff and Student Publications

Introduction: Smoking is a strong modifiable prognostic factor for lung cancer survival. We compared eight smoking metrics to determine which metric best models the relationship between smoking exposure with overall survival (OS) and lung cancer-specific survival (LCSS). These metrics included cigarettes-per-day, smoking duration, pack-years, square-root pack-years, logcig-years, the comprehensive smoking index, age-of-initiation, and years-since-quit.

Materials/methods: This retrospective, pooled analysis included 25 International Lung Cancer Consortium studies between June 1, 1983-December 31, 2019. The performance of smoking metrics for modelling OS was compared based on 1) strength and significance in adjusted Cox-proportional hazard models and 2) linearity based on the goodness-of-fit …

Visdb 20: A Manually Curated Resource Of Viral Integration Sites And Their Regulatory Maps In Human Diseases, Citu Citu, Ajeet Singh, Xinyi Liu, Mounika Ashannagari, Rinki Ratnapriya, Zhongming Zhao

Faculty, Staff and Student Publications

The integration of viral sequence into the human genome plays critical role in the onset of various diseases, especially cancers. To facilitate systematic analysis of these events, we present VISDB 2.0, an expanded and updated database of human viral integration sites (VISs). The current release contains more than 270,000 manually curated VISs derived from 209 peer-reviewed publications, covering 11 viruses, including four retroviruses and seven DNA viruses. This represents a 3.5-fold increase in VIS entries compared with the previous version. Each VIS record includes standardized genomic coordinates and annotations describing local genomic context, CpG islands, repetitive elements, chromosomal fragile sites, …

Radiation Doses To Cardiac Substructures Predict Elevation In High-Sensitivity Cardiac Troponin T Levels In Radiation Therapy For Lung Cancer, Xinru Chen, Xiaodong Zhang, Ting Xu, Radhe Mohan, Ruitao Lin, Mei Chen, Rachel C Maguire, Yao Zhao, Efstratios Koutroumpakis, Nicolas L Palaskas, Anita Deswal, Ali Ajdari, Joshua S Niedzielski, Sanjay S Shete, Laurence E Court, Jinzhong Yang, Zhongxing Liao

Faculty, Staff and Student Publications

Purpose: Cardiotoxicity is a major concern for patients undergoing thoracic radiation therapy. This study compared the predictive power of radiation dose-volume histogram (DVH) parameters and radiomic/dosiomic features of the whole heart (WH) and cardiac substructures for elevated circulating high-sensitivity cardiac troponin T (hs-cTnT), a biomarker for early detection of cardiac adverse events.

Methods and materials: A retrospective cohort of 160 patients with non-small cell lung cancer (NSCLC) from a completed prospective trial and a prospective cohort of 57 patients with NSCLC enrolled in an ongoing trial were analyzed. The endpoint was hs-cTnT elevation, indicated by an increase of ≥5 ng/L …

High Dietary Fiber Is Associated With Improved Outcomes In Patients With Melanoma And Sarcoma Treated With Immunotherapy Regardless Of Gut Microbiome Dysbiosis And Social Vulnerability, Brittany C Fields, Raymond S Traweek, Kai Jiang, Russell G Witt, Ashish Damania, Yi-Ju Chiang, Nadim Ajami, Elise Nassif-Haddad, Emily Z Keung, Manoj Chelvanambi, Xiaotao Zhang, Christine B Peterson, Jennifer A Wargo, Carrie R Daniel, Christina L Roland, Ashley M Holder

Faculty, Staff and Student Publications

Background: Social vulnerability, dietary fiber, and the gut microbiome have been individually implicated in clinical outcomes for melanoma and sarcoma patients. This study hypothesized that increasing social vulnerability is associated with insufficient dietary fiber intake and negatively associated with microbiome composition and clinical outcomes.

Methods: Clinicopathologic data, baseline fiber intake, and gut microbiome profiles were assessed in 153 patients with melanoma or sarcoma treated with immune checkpoint blockade (ICB) and prospectively followed. Patients' social vulnerability index (SVI) and fiber intake were evaluated for associations with microbiome composition, treatment response, and overall survival (OS).

Results: SVI percentile was 0.4 (interquartile ratio …

Ccr7 Immune Cell Receptor Expression In Inflammatory Breast Cancer, Jennifer H Chen, Wintana Balema, Savitri Krishnamurthy, Alison N Lawrence, Natalie W Fowlkes, Richard A Larson, Surbhi Shivhare, Caren Sanchez, Megan M Rodriguez, Jangsoon Lee, Emilly S Villodre, Bisrat G Debeb, Naoto T Ueno, Steve Van Laere, Francois Bertucci, Hyunwoo Cho, Erik P Sulman, Bora Lim, Wendy A Woodward

Faculty, Staff and Student Publications

No abstract provided.

Patterns Of Failure Following Stereotactic Radiosurgery Salvage For Recurrent High-Grade Glioma, Shivani Bindal, Brandon Gonzalez, Antonio Dono, Roy Riascos, Jay-Jiguang Zhu, Sigmund Hsu, Nitin Tandon, Angel Blanco, Yoshua Esquenazi, Mark Amsbaugh

Faculty, Staff and Student Publications

Background and objectives: Re-irradiation with stereotactic radiosurgery (SRS) is an increasingly used treatment for recurrent high-grade glioma (HGG). We analyzed the patterns of failure after salvage SRS to better identify which patients would most benefit.

Methods: We reviewed all patients who received SRS for recurrent HGG over 12 years at our institution. Pattern of failure was defined by the distance of recurrence from the SRS isodose line. Overall-survival (OS), progression-free survival (PFS), and local-failure-free survival (LFS) were estimated using Kaplan-Meier methods, and regression model analysis was performed to analyze clinical predictors of failure.

Results: 146 patients with HGG underwent SRS …

Pimicotinib Versus Placebo For Tenosynovial Giant Cell Tumour (Maneuver): An International, Randomised, Placebo-Controlled, Phase 3 Trial, Hairong Xu, Xiaohui Niu, Vinod Ravi, Javier Martin-Broto, Albiruni Abdul Razak, Ramy Saleh, Yong Zhou, Jingnan Shen, Tang Liu, Kamlesh Kumar Sankhala, César Serrano, Silvia Stacchiotti, Jing Wang, Giacomo G Baldi, Yi Feng, Yingqi Hua, Tao Li, Piotr Rutkowski, Xiaojing Zhang, Gabriel Tinoco, Qingping Zou, Boyao Shan, Xiangyu Zhu, Hans Gelderblom

Faculty, Staff and Student Publications

Background: Tenosynovial giant cell tumour (TGCT) is a rare, locally aggressive neoplasm that affects otherwise healthy adults. There are few systemic treatment options, highlighting an unmet need. We report the results of part 1 of the MANEUVER trial, which aimed to evaluate the efficacy and safety of pimicotinib, a highly selective, potent, colony-stimulating factor-1 receptor inhibitor, in patients with TGCT.

Methods: MANEUVER is a randomised, placebo-controlled, phase 3 study done in 40 specialised hospitals in Asia, Europe, and North America. Patients aged 18 years and older with unresectable, symptomatic TGCT (patient-reported worse stiffness or worst pain of at least 4 …

The Efficacy And Safety Of Serratus Anterior Plane Block In Patients Undergoing Cardiac Surgery: A Systematic Review And Meta-Analysis, Xu-Bo Cui, Ming-Zhu Cui, Qiu-Ju Yang, Yang Liu, Meng-Qi Yi, Xiao-Yang Zhang, Yun-Tai Yao

Faculty, Staff and Student Publications

Background: Serratus anterior plane block (SAPB) is a widely used fascial block that reduces postoperative pain and perioperative opioid consumption. This meta-analysis assessed the efficacy and safety of SAPB in cardiac surgery patients.

Methods: We systematically searched PubMed, Web of Science, Cochrane Library, Embase, China National Knowledge Infrastructure, and Wanfang databases on May 10, 2024. Pooled relative risks and mean differences (MD) with 95% confidence intervals (CI) were calculated for dichotomous and continuous outcomes, respectively. Heterogeneity was assessed using the I2 statistic, and publication bias was evaluated using Egger test. Subgroup analyses were stratified by study design (randomized controlled trials …

Uncovering Hidden Prognostic Patterns In Colorectal Cancer Histology Using Unsupervised Learning: A Computational Pathology Study, Wen-Tong Zhou, Yong Liu, Gang Yu, Kuan-Song Wang, Chao Xu, Jonathan Greenbaum, Chong Wu, Lin-Dong Jiang, Christopher J Papasian, Hong-Mei Xiao, Hong-Wen Deng

Faculty, Staff and Student Publications

Colorectal cancer (CRC) remains a leading cause of cancer mortality globally, yet current histopathological diagnostics capture only limited features. This study aimed to discover subtle, prognostically significant histomorphological patterns in CRC tissues using unsupervised deep learning. We developed a framework integrating convolutional neural networks with deep clustering, trained on 23,341 image patches from 493 patients. We identified 30 distinct histomorphological clusters from CRC tissue images. Through univariate and multivariate survival analyses, three clusters (Cluster13, Cluster19, and Cluster24) were consistently associated with patient prognosis. These clusters were integrated with clinical factors (T stage, N stage, and differentiation degree) to construct a …

Telemedicine As A Gateway To Early-Phase Oncology Trials: Lessons From 14,000 Patients And Future Directions For Global Access And Equity, Carlos Torrado, Clark R Andersen, Lei Kang, Amanda L Brink, Taiwo Adesoye, Hung Le, Clover J Patterson, Anna Poullard, Jessica A Osburn, Harold N Tan, Mohamed A Gouda, Sheena Charles, Gabriele E Urschel, Tin-Yun Tang, David S Hong, Stephane Champiat, Aung Naing, Apostolia M Tsimberidou, Ecaterina E Dumbrava, Sarina A Piha-Paul, Jordi Rodon, Timothy A Yap, Paula R Pohlmann, Funda Meric-Bernstam, Siqing Fu

Faculty, Staff and Student Publications

Background: Telemedicine expanded rapidly during the COVID-19 pandemic, but its role in early-phase oncology trials remains uncertain. We evaluated its impact on recruitment, enrollment, equity, and access in a large phase I program.

Patients and methods: We retrospectively analyzed patients seen for first consultation in the MD Anderson Phase I Program (2016-2023). Recruitment (consent) and enrollment (treatment initiation) were compared by visit type, race/ethnicity, and geography across pre-pandemic (2016-2019), pandemic (2020-March 11, 2023), and post-public health emergency (PHE; March-December 2023) periods. A chart review of 400 patients validated findings.

Results: Of 14,085 patients, 7,247 were evaluated post-pandemic, with 36% (n …

Pan-Cancer Evolution Signatures Link Clonal Expansion To Dynamic Changes In The Tumor Immune Microenvironment, Xinyu Yang, Wei Liu, Geoff Macintyre, Peter Van Loo, Florian Markowetz, Peter Bailey, Ke Yuan

Faculty, Staff and Student Publications

Cancer is an evolutionary process characterized by profound intratumor heterogeneity (ITH), which can be quantified using in silico estimates of cancer cell fractions (CCFs) of tumor-specific somatic mutations. We demonstrate a data-driven approach based on CCF distributions to identify 4 robust pan-cancer evolutionary signatures from 4,146 tumors across 17 cancer types in The Cancer Genome Atlas (TCGA). These signatures define a continuum of cancer cell fractions reflecting neutral evolution, clonal expansion, and clonal fixation. Correlating evolutionary signatures with mutational and biological programs reveals that tumors enriched for clonal expansion and fixation are associated with immune evasion and distinct changes in …

Complete Genome Sequence Of The Widely Used Coaggregation Fusobacterial Strain Pk1594, Bibek G C, Shiqi Xu, Chenggang Wu

Faculty, Staff and Student Publications

We report the complete genome sequence of the fusobacterial strain PK1594, widely used to study coaggregation between Fusobacterium nucleatum and oral bacteria. The assembly comprises a 2,357,192-bp chromosome and a 20,441-bp contig representing a duplicated 10,221-bp plasmid. znpA analysis indicates that PK1594 is Fusobacterium hwasookii rather than F. nucleatum.

Pkmζ-Kibra Interactions, Molecular Turnover, And Memory, Changchi Hsieh, David A Cano, Panayiotis Tsokas, James E Cottrell, André Antonio Fenton, Harel Shouval, Todd Charlton Sacktor

Faculty, Staff and Student Publications

How can the molecules that strengthen synaptic connections maintain memory in the face of molecular turnover? Our previous work showed that persistent interaction between the postsynaptic scaffolding protein, KIBRA, and the autonomously active PKC isoform, PKMζ, is crucial for maintaining synaptic long-term potentiation (LTP) and memory lasting at least a month. This duration is longer than the lifespans of individual KIBRA and PKMζ molecules. Biophysical modeling of the interaction suggests oligomers of KIBRA-PKMζ dimers, but not individual dimers or monomers, can overcome molecular turnover by continuously incorporating newly synthesized KIBRA and PKMζ, replacing those that have degraded. Here we used …

Schistosome Esophageal Gland Factor Meg-82 Drives Host Cell Lysis And Interacts With Host Immune Proteins, Pallavi Yadav, Sabona B Simbassa, Ryan Sloan, Phillip A Newmark, Jayhun Lee

Faculty, Staff and Student Publications

Schistosomes are blood flukes that ingest large amounts of host blood during their intra-mammalian stage. The ingested blood contains leukocytes that can be harmful, yet the parasites survive inside the host for decades, reflecting superb immune evasion mechanisms that remain poorly understood. Our previous work discovered that FoxA, a forkhead transcription factor, drives the production of the esophageal gland, an anterior digestive organ essential for degrading ingested leukocytes and for in vivo survival. However, a comprehensive molecular makeup of the esophageal gland remains unclear. Importantly, the esophageal gland factors responsible for degrading ingested leukocytes, their mechanisms of action, and how …

Clinical Trial Success Rate In Lymphoma: Fate Of Trials And Agents From 2000 To 2019, Zhiping Luo, Meng Li, Brian C Primeaux, Rahul Shah, Ruitao Lin, Swaminathan P Iyer, Loretta J Nastoupil, Michael R Green, Jason R Westin, Christopher R Flowers, Dai Chihara

Faculty, Staff and Student Publications

Although previous studies have examined the drug development and clinical trial success rates in oncology, a comprehensive analysis of development success rate in lymphoma has not been performed. Therefore, we analyzed lymphoma trials initiated between 1 January 2000 and 31 December 2019, using the Trialtrove database and ClinicalTrials.gov. We identified phase 1, 2, and 3 trials that included patients with lymphoma and analyzed the transition rate of investigational agents across phases and their US Food and Drug Administration (FDA) approval rates to assess the efficiency and success of the clinical development process. A total of 1032 phase 1 trials and …

International Consensus-Driven Recommendations For Patient-Reported Outcome Research Objectives In Early Phase Dose-Finding Oncology Trials: Optimise-Ror, Emily Alger, Olalekan Lee Aiyegbusi, Amylou C Dueck, Anna Minchom, Madeline Pe, John D Peipert, Claire Snyder, Stefan N Symeonides, Roger Wilson, Ethan Basch, Yu Qiao, Susan E Bates, Helen Bulbeck, Lizzie Dean, Massimo Di Maio, Aaron R Hansen, Olga Kholmanskikh, Ken Kobayashi, Dónal Landers, Christophe Le Tourneau, J Jack Lee, Brigette B Y Ma, Lynley V Marshall, Sheetal Patel, Joan Petrie, Gregory R Pond, Kieran Prior, Khadija R Rantell, John F Reeve, Olga Solovyeva, Nolan A Wages, Harald A Weber, Melanie J Calvert, Christina Yap

Faculty, Staff and Student Publications

Purpose: There is growing scientific interest in incorporating patient-reported outcomes (PROs) in early phase dose-finding oncology trials (DFOTs) to assess tolerability, inform dose selection, and guide later stage trial design. However, research indicates that PRO objectives in DFOTs are often unclear. The Incorporating Patient-Reported Outcomes in Dose-Finding Trials-Research Objectives Recommendations (OPTIMISE-ROR) project was established to support trialists to effectively incorporate PROs into DFOTs.

Methods: Using the Enhancing Quality and Transparency of Health Research (EQUATOR) Network's methodological framework, guideline development included the following: (1) a methodological review of published DFOTs incorporating PROs; (2) candidate item generation, refined through expert consultation; (3) …

Dual Phagocytosis-Checkpoint Blockade Revitalizes Immune Surveillance In Mouse Models Of Glioblastoma, Jonghoon Ha, Yifan Wang, Yifan Ma, Annette Wu, Shiyan Dong, Seong Dong Jeong, Jared L Edwards, Mengyu Chang, Yen-Tzu Chang, Xiaotian Wang, Maurice Dufilho, Michelle Najarro Torres, Shannon Mccabe, Weiye Deng, Adam J Grippin, Jeffrey S Weinberg, Shaan M Raza, Franco Demonte, Ian E Mccutcheon, Sujit Prabhu, Sherise D Ferguson, Chibawanye I Ene, Kadir Akdemir, Sreyashi Basu, Sonali Jindal, Benjamin R Schrank, Jian Hu, Sangeeta Goswami, Vinay K Puduvalli, Frederick F Lang, Kristin Huntoon, Padmanee Sharma, Betty Y S Kim, Wen Jiang

Faculty, Staff and Student Publications

Macrophage-mediated phagocytosis of tumor cells elicits potent antitumor immunity. Nonetheless, sole-blockade of the anti-phagocytosis molecule CD47 has yielded insufficient therapeutic outcomes. Here, we report that glioblastoma (GBM) cells expressed abundant levels of phagocytosis checkpoint CD24. We further show that dual blockade of CD24 and CD47 synergistically enhances the pro-phagocytic activity of macrophages, thereby improving tumor antigen cross-presentation and activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. This innate immune activation facilitates T cell infiltration into tumors and sensitizes tumors to anti-PD1 therapy, improving survival outcomes in murine GBM models, including immunosuppressive tumors reflecting human GBM-like features. Thus, our …